Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for the preparation of montelukast acid and sodium salt thereof in amorphous form

a technology of montelukast and sodium salt, which is applied in the field of improved methods for the preparation of montelukast acid and its sodium salt, and the method for the preparation of amorphous montelukast sodium, can solve the problems of obvious long process as well as tedious, capital-intensive freeze-drying equipment, and proves commercially expensive if not unviabl

Active Publication Date: 2007-04-12
MOREPEN LAB LTD
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] It is, therefore, an object of the present invention to provide an efficient method for the preparation of Montelukast sodium (I) in amorphous form, which eliminates the major problems associated with the prior arts.
[0014] Another object of the present invention is to provide a time and cost effective method for the preparation of montelukast sodium salt (I) in amorphous form.
[0015] Yet another object of the present invention is to provide a simple method for the isolation of pure crystalline montelukast acid and its subsequent conversion into montelukast sodium (I) In Amorphous Form.

Problems solved by technology

The process is obviously lengthy as well as tedious since it requires chromatographic purification of both the methyl ester (V) and montelukast acid (VI).
Further, it also requires capital-intensive freeze-drying equipment and thus proves to be commercially expensive if not unviable.
The process is not suitable for large-scale production, as it requires tedious chromatographic purification of intermediates and freeze-drying of Montelukast sodium (I).
Moreover, the yields of the intermediates are also low.
This is a risky process requiring capital intensive cold room facility, constant careful handling as accidental rise in temperature during this lengthy drying procedure could either lead to the formation of impurities which may be carried forward to the next stage or result in complete decomposition of the expensive advanced intermediate.
As is clear from the above discussions, both the routes (Processes A and B) for the synthesis of montelukast sodium suffer from several drawbacks and involve steps that are lengthy, tedious, non-reproducible and require stringent conditions and high capital infrastructure.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for the preparation of montelukast acid and sodium salt thereof in amorphous form
  • Method for the preparation of montelukast acid and sodium salt thereof in amorphous form
  • Method for the preparation of montelukast acid and sodium salt thereof in amorphous form

Examples

Experimental program
Comparison scheme
Effect test

example-1

[(S)-(E)]-2-[2-[3-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]3-methanesulphonyloxy]propyl]phenyl]-2-propanol (VIII)

[0066] To a 2.0 lt. / 4 neck round bottom flask fitted with a mechanical stirrer and thermometer inlet were successively charged diol (VII) (75.0 g, 0.16 mol), toluene (225 ml) and acetonitrile (600 ml) under an atmosphere of nitrogen gas at +25 to +35° C. After stirring for approximately 10 minutes, N,N-diisopropylethylamine (23.29g / 30.90 ml, 0.18 mol) was added over a period of 5 minutes. The solution was cooled to −30 to −25° C. in a liquid N2 / methanol bath, methanesulphonyl chloride (33.0g / 22.5 ml, 0.29 mol) was added drop wise over a period of 15 minutes, keeping the temperature at −30 to −25° C. and stirred for 5 hrs at this temperature. During this period, thick off white to pale yellow solid had precipitated out. The reaction mixture was further cooled to −30 to −40° C., product (VIII) was carefully filtered, successively washed with chilled acetonitrile (−30° C...

example-2

[(R)-(E)-1-[[[-1-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methyl ethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid dicyclohexylamine salt (X)

[0069] Step 1

[0070] n-Butyl lithium (195 ml, 1.6 Molar solution in hexanes, 0.312 mol.) was slowly added to a cooled (−15 to −10° C.) solution of 1-(mercaptomethyl)cyclopropaneacetic acid (IX) (23.25 g, 0.16 mol.) in dry THF (385 ml.) in a 1 lt. / 4 neck round bottom flask fitted with a mechanical stirrer and a thermometer inlet under nitrogen atmosphere and the mixture was stirred for 30 minutes at −15 to −10° C.

[0071] Step 2

[0072] To a separate a 1.0 lt / 4 neck round bottom flask equipped with a mechanical stirrer, thermometer inlet and under dry nitrogen gas atmosphere was placed THF (385 ml) and the solvent was cooled to −10 to −5° C. The wet monomesylate (VIII) (77.0 g, 0.144 mol / amount calculated on dry basis after LOD analysis) was added via a powder funnel and the mixture was stirred for 15 minutes at −10 to...

example-3

[(R)-(E)-1-[[[-1-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (Pure VI)

[0082] To a stirred suspension of montelukast DCHA salt (X) (80.0 g, 0.104 mol, purity 98.06%, assay=97.50.%), in toluene (800 ml.) and DM water (800 ml.) at +25 to +35° C., acetic acid (2.0 Molar soln., 80 ml.) was charged over a period of 30 minutes and the mixture was stirred for another 15 minutes at +25 to +35° C. The toluene layer was separated, washed with water (800 ml). The toluene layer was separated, seeded with crystals of pure (VI) and stirred at +25 to +35° C. for 5-6 hrs. The resulting solid was filtered, washed with toluene (160 ml) and dried at +40 to +45° C. under vacuum to yield pure montelukast acid (VI) as a light yellow solid. Yield=37.0 g (60.54%); Purity (HPLC)=98.95%; Assay (HPLC)=99.01%; Melting point=148-150° C.

[0083] IR (KBr, cm−1)=3573.1, 2988.2, 2919.6, 1716.0, 1606.7, 1500.1, 1407.8, 1076.0, 842.3, 766...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Temperatureaaaaaaaaaa
Temperatureaaaaaaaaaa
Temperatureaaaaaaaaaa
Login to View More

Abstract

A method for the preparation of montelukast acid sodium salt thereof in amorphous form has been described. The method comprises of following steps: (a) generating the dilithium dianion of 1-(mercaptomethyl)cyclopropane acetic acid, by reacting with alkyl lithium, (b) coupling the said dianion with wet mesylate to get montelukast acid in crude form, (c) obtaining DCHA salt in crude form by adding dicyclohexylamine (DCHA) to crude acid obtained in the above step (b), (d) purifying and converting the said DCHA salt in crude form, to montelukast acid in pure form, and (e) reacting the pure montelukast acid in a polar protic solvent with a source of sodium ion followed by evaporating the solvent and triturating of the residue with non-polar water immiscible solvent.

Description

FIELD OF THE INVENTION [0001] This invention relates to an improved method for the preparation of Montelukast acid and its sodium salt [0002] The present invention particularly relates to a method for the preparation of amorphous Montelukast sodium. Further, the invention relates to an improved method that is industrially feasible and commercially profitable. More particularly the present invention relates to a method for the isolation of pure crystalline montelukast acid and its subsequent conversion into amorphous montelukast sodium. The conversion is carried out by using a mixture of polar protic and water immiscible nonpolar solvent system. The method results in the production of montelukast sodium in amorphous form with high purity, low residual solvent content and comparable yield. BACKGROUND OF THE INVENTION [0003] The leukotrienes are potent inflammatory mediators which may have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowel disease and asthma....

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): A61K31/47C07D215/04C07D215/18
CPCC07D215/18
Inventor SURI, SANJAYSINGH, JUJHARSINGH, GURDEEPTAMVAR, MADAN PALMAHENDRU, MANU
Owner MOREPEN LAB LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com